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Quizartinib can prolong OS in rel/ref, FLT3-ITD AML
STOCKHOLM—Phase 3 results suggest the FLT3 inhibitor quizartinib can prolong overall survival (OS) in patients with relapsed/refractory, FLT3-ITD acute myeloid leukemia (AML).
In the QuANTUM-R study, patients who received single-agent quizartinib had a significantly longer median OS than patients who received salvage chemotherapy.
There was a trend toward improved event-free survival (EFS) with quizartinib as well.
“QuANTUM-R represents the first study that shows a significant improvement in overall survival for a single agent—a FLT3 inhibitor or any other targeted agent—in this population of FLT3-mutated AML patients with refractory or relapsed disease . . .,” said study investigator Jorge Cortes, MD, of MD Anderson Cancer Center in Houston, Texas.
Dr Cortes presented results from QuANTUM-R at the 23rd Congress of the European Hematology Association (EHA). The research was selected as the best late-breaking abstract (LB2600).
The study was funded by Daiichi Sankyo, Inc., and Dr Cortes is a consultant for the company.
Patients and treatment
QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete remission. They had received at least 1 cycle of an induction regimen containing standard-dose anthracycline or mitoxantrone.
Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).
Responders could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.
Baseline characteristics were similar between the treatment arms. The median age was 55 (range, 19-81) for patients receiving quizartinib and 58 (range, 18-78) for those receiving chemotherapy.
Thirty-three percent of the quizartinib arm had refractory disease, and 67% had relapsed disease. Thirty-four percent of the chemotherapy arm had refractory disease, and 66% had relapsed disease.
The percentage of patients with a prior allogeneic HSCT was 25% in the quizartinib arm and 23% in the chemotherapy arm. Most patients in both arms had intermediate-risk cytogenetics—78% of the quizartinib arm and 66% of the chemotherapy arm.
In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.
The median treatment duration was 4 cycles (range, 1-3) in the quizartinib arm and 1 cycle (range, 1-2) for patients who received LoDAC, MEC, and FLAG-IDA.
The most common reason for discontinuation of chemotherapy was lack of response/progression (n=49), followed by death (n=6). Twenty-four patients completed salvage chemotherapy.
In the quizarinib arm, the most common reasons for treatment discontinuation were HSCT (n=79), relapse (n=60), or lack of response/progression (n=47).
Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.
Results
The median follow-up was 23.5 months. The efficacy results include all randomized patients, and the safety results include only those who received their assigned treatment.
The study’s primary endpoint was OS. The median OS was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year OS rate was 27% and 20%, respectively.
The median EFS was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071). Dr Cortes noted that patients who did not receive treatment were censored on day 1, and partial responses were counted as failures in the EFS analysis.
The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm.
The composite complete response (CR) rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes the CR rate (4% and 1%, respectively), the rate of CR with incomplete platelet recovery (4% and 0%, respectively), and the rate of CR with incomplete hematologic recovery (40% and 26%, respectively). The rate of partial response was 21% and 3%, respectively.
Dr Cortes said rates of treatment-emergent adverse events (TEAEs) were similar between the treatment arms.
Grade 3 or higher hematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included thrombocytopenia (35% and 34%), anemia (30% and 29%), neutropenia (32% and 25%), febrile neutropenia (31% and 21%), and leukopenia (17% and 16%).
Grade 3 or higher nonhematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included fatigue (8% and 1%), hypokalemia (12% and 9%), sepsis/septic shock (16% and 18%), dyspnea (5% for both), hypophosphatemia (5% for both), and pneumonia (12% and 9%).
Three percent of patients in the quizartinib arm had grade 3 QTcF prolongation, but there were no grade 4 cases. Two patients discontinued quizartinib due to QTcF prolongation.
“The safety of this drug has remained constant across over 1600 patients that have been treated with quizartinib across a variety of studies,” Dr Cortes said.
He added that QuANTUM-R results open up the possibility that quizartinib could be used in other settings. Researchers are already testing standard chemotherapy with and without quizartinib in a phase 3 trial of patients with newly diagnosed, FLT-ITD AML (QuANTUM-First).
STOCKHOLM—Phase 3 results suggest the FLT3 inhibitor quizartinib can prolong overall survival (OS) in patients with relapsed/refractory, FLT3-ITD acute myeloid leukemia (AML).
In the QuANTUM-R study, patients who received single-agent quizartinib had a significantly longer median OS than patients who received salvage chemotherapy.
There was a trend toward improved event-free survival (EFS) with quizartinib as well.
“QuANTUM-R represents the first study that shows a significant improvement in overall survival for a single agent—a FLT3 inhibitor or any other targeted agent—in this population of FLT3-mutated AML patients with refractory or relapsed disease . . .,” said study investigator Jorge Cortes, MD, of MD Anderson Cancer Center in Houston, Texas.
Dr Cortes presented results from QuANTUM-R at the 23rd Congress of the European Hematology Association (EHA). The research was selected as the best late-breaking abstract (LB2600).
The study was funded by Daiichi Sankyo, Inc., and Dr Cortes is a consultant for the company.
Patients and treatment
QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete remission. They had received at least 1 cycle of an induction regimen containing standard-dose anthracycline or mitoxantrone.
Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).
Responders could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.
Baseline characteristics were similar between the treatment arms. The median age was 55 (range, 19-81) for patients receiving quizartinib and 58 (range, 18-78) for those receiving chemotherapy.
Thirty-three percent of the quizartinib arm had refractory disease, and 67% had relapsed disease. Thirty-four percent of the chemotherapy arm had refractory disease, and 66% had relapsed disease.
The percentage of patients with a prior allogeneic HSCT was 25% in the quizartinib arm and 23% in the chemotherapy arm. Most patients in both arms had intermediate-risk cytogenetics—78% of the quizartinib arm and 66% of the chemotherapy arm.
In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.
The median treatment duration was 4 cycles (range, 1-3) in the quizartinib arm and 1 cycle (range, 1-2) for patients who received LoDAC, MEC, and FLAG-IDA.
The most common reason for discontinuation of chemotherapy was lack of response/progression (n=49), followed by death (n=6). Twenty-four patients completed salvage chemotherapy.
In the quizarinib arm, the most common reasons for treatment discontinuation were HSCT (n=79), relapse (n=60), or lack of response/progression (n=47).
Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.
Results
The median follow-up was 23.5 months. The efficacy results include all randomized patients, and the safety results include only those who received their assigned treatment.
The study’s primary endpoint was OS. The median OS was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year OS rate was 27% and 20%, respectively.
The median EFS was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071). Dr Cortes noted that patients who did not receive treatment were censored on day 1, and partial responses were counted as failures in the EFS analysis.
The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm.
The composite complete response (CR) rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes the CR rate (4% and 1%, respectively), the rate of CR with incomplete platelet recovery (4% and 0%, respectively), and the rate of CR with incomplete hematologic recovery (40% and 26%, respectively). The rate of partial response was 21% and 3%, respectively.
Dr Cortes said rates of treatment-emergent adverse events (TEAEs) were similar between the treatment arms.
Grade 3 or higher hematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included thrombocytopenia (35% and 34%), anemia (30% and 29%), neutropenia (32% and 25%), febrile neutropenia (31% and 21%), and leukopenia (17% and 16%).
Grade 3 or higher nonhematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included fatigue (8% and 1%), hypokalemia (12% and 9%), sepsis/septic shock (16% and 18%), dyspnea (5% for both), hypophosphatemia (5% for both), and pneumonia (12% and 9%).
Three percent of patients in the quizartinib arm had grade 3 QTcF prolongation, but there were no grade 4 cases. Two patients discontinued quizartinib due to QTcF prolongation.
“The safety of this drug has remained constant across over 1600 patients that have been treated with quizartinib across a variety of studies,” Dr Cortes said.
He added that QuANTUM-R results open up the possibility that quizartinib could be used in other settings. Researchers are already testing standard chemotherapy with and without quizartinib in a phase 3 trial of patients with newly diagnosed, FLT-ITD AML (QuANTUM-First).
STOCKHOLM—Phase 3 results suggest the FLT3 inhibitor quizartinib can prolong overall survival (OS) in patients with relapsed/refractory, FLT3-ITD acute myeloid leukemia (AML).
In the QuANTUM-R study, patients who received single-agent quizartinib had a significantly longer median OS than patients who received salvage chemotherapy.
There was a trend toward improved event-free survival (EFS) with quizartinib as well.
“QuANTUM-R represents the first study that shows a significant improvement in overall survival for a single agent—a FLT3 inhibitor or any other targeted agent—in this population of FLT3-mutated AML patients with refractory or relapsed disease . . .,” said study investigator Jorge Cortes, MD, of MD Anderson Cancer Center in Houston, Texas.
Dr Cortes presented results from QuANTUM-R at the 23rd Congress of the European Hematology Association (EHA). The research was selected as the best late-breaking abstract (LB2600).
The study was funded by Daiichi Sankyo, Inc., and Dr Cortes is a consultant for the company.
Patients and treatment
QuANTUM-R enrolled adults with FLT3-ITD AML (at least 3% FLT3-ITD allelic ratio) who had refractory disease or had relapsed within 6 months of their first complete remission. They had received at least 1 cycle of an induction regimen containing standard-dose anthracycline or mitoxantrone.
Patients were randomized to receive once-daily treatment with quizartinib (n=245) or a salvage chemotherapy regimen (n=122)—low-dose cytarabine (LoDAC, n=29); combination mitoxantrone, etoposide, and cytarabine (MEC, n=40); or combination fludarabine, cytarabine, and idarubicin (FLAG-IDA, n=53).
Responders could proceed to hematopoietic stem cell transplant (HSCT), and those in the quizartinib arm could resume quizartinib after HSCT.
Baseline characteristics were similar between the treatment arms. The median age was 55 (range, 19-81) for patients receiving quizartinib and 58 (range, 18-78) for those receiving chemotherapy.
Thirty-three percent of the quizartinib arm had refractory disease, and 67% had relapsed disease. Thirty-four percent of the chemotherapy arm had refractory disease, and 66% had relapsed disease.
The percentage of patients with a prior allogeneic HSCT was 25% in the quizartinib arm and 23% in the chemotherapy arm. Most patients in both arms had intermediate-risk cytogenetics—78% of the quizartinib arm and 66% of the chemotherapy arm.
In all, 241 patients received quizartinib, and 94 received salvage chemotherapy—LoDAC (n=22), MEC (n=25), and FLAG-IDA (n=47). Of the 28 patients in the chemotherapy group who were not treated, most withdrew consent.
The median treatment duration was 4 cycles (range, 1-3) in the quizartinib arm and 1 cycle (range, 1-2) for patients who received LoDAC, MEC, and FLAG-IDA.
The most common reason for discontinuation of chemotherapy was lack of response/progression (n=49), followed by death (n=6). Twenty-four patients completed salvage chemotherapy.
In the quizarinib arm, the most common reasons for treatment discontinuation were HSCT (n=79), relapse (n=60), or lack of response/progression (n=47).
Thirty-two percent of quizartinib-treated patients and 12% of the chemotherapy group went on to HSCT.
Results
The median follow-up was 23.5 months. The efficacy results include all randomized patients, and the safety results include only those who received their assigned treatment.
The study’s primary endpoint was OS. The median OS was 6.2 months in the quizartinib arm and 4.7 months in the chemotherapy arm (hazard ratio=0.76, P=0.0177). The 1-year OS rate was 27% and 20%, respectively.
The median EFS was 6.0 weeks in the quizartinib arm and 3.7 weeks in the chemotherapy arm (hazard ratio=0.90, P=0.1071). Dr Cortes noted that patients who did not receive treatment were censored on day 1, and partial responses were counted as failures in the EFS analysis.
The overall response rate was 69% in the quizartinib arm and 30% in the chemotherapy arm.
The composite complete response (CR) rate was 48% in the quizartinib arm and 27% in the chemotherapy arm. This includes the CR rate (4% and 1%, respectively), the rate of CR with incomplete platelet recovery (4% and 0%, respectively), and the rate of CR with incomplete hematologic recovery (40% and 26%, respectively). The rate of partial response was 21% and 3%, respectively.
Dr Cortes said rates of treatment-emergent adverse events (TEAEs) were similar between the treatment arms.
Grade 3 or higher hematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included thrombocytopenia (35% and 34%), anemia (30% and 29%), neutropenia (32% and 25%), febrile neutropenia (31% and 21%), and leukopenia (17% and 16%).
Grade 3 or higher nonhematologic TEAEs occurring in at least 5% of patients (in the quizartinib and chemotherapy groups, respectively) included fatigue (8% and 1%), hypokalemia (12% and 9%), sepsis/septic shock (16% and 18%), dyspnea (5% for both), hypophosphatemia (5% for both), and pneumonia (12% and 9%).
Three percent of patients in the quizartinib arm had grade 3 QTcF prolongation, but there were no grade 4 cases. Two patients discontinued quizartinib due to QTcF prolongation.
“The safety of this drug has remained constant across over 1600 patients that have been treated with quizartinib across a variety of studies,” Dr Cortes said.
He added that QuANTUM-R results open up the possibility that quizartinib could be used in other settings. Researchers are already testing standard chemotherapy with and without quizartinib in a phase 3 trial of patients with newly diagnosed, FLT-ITD AML (QuANTUM-First).
Anti-CD22 CAR T rescues kids with ALL after CD19 failure
STOCKHOLM, SWEDEN – A novel chimeric antigen receptor T-cell construct directed against CD22 was able to rescue children with relapsed or refractory B-cell acute lymphoblastic leukemia for whom CD19-directed CAR T therapy had failed, investigators from China reported.
Thirty days after CAR T cell infusion, 12 of 15 children (80%) treated with the unnamed CD22 CAR T product had a complete response (CR) and one (6.7%) had a partial response (PR), for an overall response rate (ORR) of 86.7%, said Jing Pan, MD, from the Beijing Boren Hospital in China.
Surprisingly for a therapy of its type, the CD22 CAR T was well tolerated, with only mild cases of the cytokine release syndrome (CRS), and it could be delivered safely in children with relapsed disease after hematopoietic cell transplants (HCT), she reported in a briefing and in an oral abstract session at the annual congress of the European Hematology Association.
“CD22 CAR T immunotherapy brings hope for patients with refractory or relapsed B-ALL who failed on CD19 CAR T immunotherapy, and we think it’s quite safe. No children died and no children had severe side effects during the study, even in post-HCT patients,” Dr. Pan said.
She noted that in a previous clinical trial by her group, some patients experienced relapses and were resistant to retreatment with CD19-directed CAR T therapy due to mutations or loss of the CD19 antigen (Leukemia. 2017 Dec;31[12]:2587-93).
Since CD22 is highly expressed on leukemic cells in children with B-ALL, the investigators decided to evaluate the safety and efficacy of a CD22 CAR T as a rescue strategy. They enrolled 15 patients who either experienced relapse or did not have a response to CD19 CAR T immunotherapy. The CAR T construct they used contains an anti-CD22 single-chain variable fragment derived from a humanized CD22 antibody.
Patient conditioning with fludarabine and cyclophosphamide was performed simultaneously with CAR T transfection and expansion. After about 7 days, the expanded and transformed CAR T cells were infused at a dose of 8.2 x 105/kg in patients who had not undergone HCT, and 0.9 x 105 in patients who had received a transplant.
The patients ranged from 2 to 18 years old (median 8 years), had a median disease course of 21 months (range 5-84 months), and had a median of 42% bone marrow blasts (range 5%-95.5%).
Four of the 15 patients had relapses following allogeneic HCT, and the remaining 11 had relapses following chemotherapy. Two of the patients were found to be minimal residual disease (MRD)-positive by flow cytometry. Two patients had extramedullary disease only at relapse.
Ten of 11 patients who had experienced a hematologic relapse had either a CR or CR with incomplete recovery of counts (CRi), and of these 10 patients, nine were determined on follow-up to be MRD-negative by flow cytometry.
One of the two patients with extramedullary disease had a CR, and the other had a partial response.
Although two patients had no response to CD22 CAR T therapy, expression of the antigen was strong on leukemia cells from these patients, Dr. Pan said.
All patients experienced CRS, but none had greater than grade 2, Dr. Pan said, although she did not provide give specific numbers. Two patients had grade 1 neurotoxicity, two patients had grade 2 hypoxemia, and one patient had grade 2 liver enzyme elevation.
At a median follow-up of 108 days, six patients had been bridged to allogeneic HCT, and eleven of 12 patients who had a CR or CRi at 30 days had no evidence of disease progression. The remaining patient with an initial CR or CRi had a relapse at day 50. The 6-month progression-free survival rate was 91.7%.
Anton Hagenbeek, MD, PhD, from the Academic Medical Center at the University of Amsterdam, the Netherlands, who moderated the briefing but was not involved in the study, commented that given the high leukemia burden of the patients and the apparent efficacy of the therapy, one would expect to see higher grades of CRS, and asked Dr. Pan whether she could account for the CRS findings in her study, compared with those of trials for CD19-directed CAR T therapy.
It may have to do with differences in density of CD22 expression, compared with CD19 expression on leukemia cells, or on differences in the antibody used to target the cells, Dr. Pan said.
SOURCE: Pan J et al. EHA Congress, Abstract S832.
STOCKHOLM, SWEDEN – A novel chimeric antigen receptor T-cell construct directed against CD22 was able to rescue children with relapsed or refractory B-cell acute lymphoblastic leukemia for whom CD19-directed CAR T therapy had failed, investigators from China reported.
Thirty days after CAR T cell infusion, 12 of 15 children (80%) treated with the unnamed CD22 CAR T product had a complete response (CR) and one (6.7%) had a partial response (PR), for an overall response rate (ORR) of 86.7%, said Jing Pan, MD, from the Beijing Boren Hospital in China.
Surprisingly for a therapy of its type, the CD22 CAR T was well tolerated, with only mild cases of the cytokine release syndrome (CRS), and it could be delivered safely in children with relapsed disease after hematopoietic cell transplants (HCT), she reported in a briefing and in an oral abstract session at the annual congress of the European Hematology Association.
“CD22 CAR T immunotherapy brings hope for patients with refractory or relapsed B-ALL who failed on CD19 CAR T immunotherapy, and we think it’s quite safe. No children died and no children had severe side effects during the study, even in post-HCT patients,” Dr. Pan said.
She noted that in a previous clinical trial by her group, some patients experienced relapses and were resistant to retreatment with CD19-directed CAR T therapy due to mutations or loss of the CD19 antigen (Leukemia. 2017 Dec;31[12]:2587-93).
Since CD22 is highly expressed on leukemic cells in children with B-ALL, the investigators decided to evaluate the safety and efficacy of a CD22 CAR T as a rescue strategy. They enrolled 15 patients who either experienced relapse or did not have a response to CD19 CAR T immunotherapy. The CAR T construct they used contains an anti-CD22 single-chain variable fragment derived from a humanized CD22 antibody.
Patient conditioning with fludarabine and cyclophosphamide was performed simultaneously with CAR T transfection and expansion. After about 7 days, the expanded and transformed CAR T cells were infused at a dose of 8.2 x 105/kg in patients who had not undergone HCT, and 0.9 x 105 in patients who had received a transplant.
The patients ranged from 2 to 18 years old (median 8 years), had a median disease course of 21 months (range 5-84 months), and had a median of 42% bone marrow blasts (range 5%-95.5%).
Four of the 15 patients had relapses following allogeneic HCT, and the remaining 11 had relapses following chemotherapy. Two of the patients were found to be minimal residual disease (MRD)-positive by flow cytometry. Two patients had extramedullary disease only at relapse.
Ten of 11 patients who had experienced a hematologic relapse had either a CR or CR with incomplete recovery of counts (CRi), and of these 10 patients, nine were determined on follow-up to be MRD-negative by flow cytometry.
One of the two patients with extramedullary disease had a CR, and the other had a partial response.
Although two patients had no response to CD22 CAR T therapy, expression of the antigen was strong on leukemia cells from these patients, Dr. Pan said.
All patients experienced CRS, but none had greater than grade 2, Dr. Pan said, although she did not provide give specific numbers. Two patients had grade 1 neurotoxicity, two patients had grade 2 hypoxemia, and one patient had grade 2 liver enzyme elevation.
At a median follow-up of 108 days, six patients had been bridged to allogeneic HCT, and eleven of 12 patients who had a CR or CRi at 30 days had no evidence of disease progression. The remaining patient with an initial CR or CRi had a relapse at day 50. The 6-month progression-free survival rate was 91.7%.
Anton Hagenbeek, MD, PhD, from the Academic Medical Center at the University of Amsterdam, the Netherlands, who moderated the briefing but was not involved in the study, commented that given the high leukemia burden of the patients and the apparent efficacy of the therapy, one would expect to see higher grades of CRS, and asked Dr. Pan whether she could account for the CRS findings in her study, compared with those of trials for CD19-directed CAR T therapy.
It may have to do with differences in density of CD22 expression, compared with CD19 expression on leukemia cells, or on differences in the antibody used to target the cells, Dr. Pan said.
SOURCE: Pan J et al. EHA Congress, Abstract S832.
STOCKHOLM, SWEDEN – A novel chimeric antigen receptor T-cell construct directed against CD22 was able to rescue children with relapsed or refractory B-cell acute lymphoblastic leukemia for whom CD19-directed CAR T therapy had failed, investigators from China reported.
Thirty days after CAR T cell infusion, 12 of 15 children (80%) treated with the unnamed CD22 CAR T product had a complete response (CR) and one (6.7%) had a partial response (PR), for an overall response rate (ORR) of 86.7%, said Jing Pan, MD, from the Beijing Boren Hospital in China.
Surprisingly for a therapy of its type, the CD22 CAR T was well tolerated, with only mild cases of the cytokine release syndrome (CRS), and it could be delivered safely in children with relapsed disease after hematopoietic cell transplants (HCT), she reported in a briefing and in an oral abstract session at the annual congress of the European Hematology Association.
“CD22 CAR T immunotherapy brings hope for patients with refractory or relapsed B-ALL who failed on CD19 CAR T immunotherapy, and we think it’s quite safe. No children died and no children had severe side effects during the study, even in post-HCT patients,” Dr. Pan said.
She noted that in a previous clinical trial by her group, some patients experienced relapses and were resistant to retreatment with CD19-directed CAR T therapy due to mutations or loss of the CD19 antigen (Leukemia. 2017 Dec;31[12]:2587-93).
Since CD22 is highly expressed on leukemic cells in children with B-ALL, the investigators decided to evaluate the safety and efficacy of a CD22 CAR T as a rescue strategy. They enrolled 15 patients who either experienced relapse or did not have a response to CD19 CAR T immunotherapy. The CAR T construct they used contains an anti-CD22 single-chain variable fragment derived from a humanized CD22 antibody.
Patient conditioning with fludarabine and cyclophosphamide was performed simultaneously with CAR T transfection and expansion. After about 7 days, the expanded and transformed CAR T cells were infused at a dose of 8.2 x 105/kg in patients who had not undergone HCT, and 0.9 x 105 in patients who had received a transplant.
The patients ranged from 2 to 18 years old (median 8 years), had a median disease course of 21 months (range 5-84 months), and had a median of 42% bone marrow blasts (range 5%-95.5%).
Four of the 15 patients had relapses following allogeneic HCT, and the remaining 11 had relapses following chemotherapy. Two of the patients were found to be minimal residual disease (MRD)-positive by flow cytometry. Two patients had extramedullary disease only at relapse.
Ten of 11 patients who had experienced a hematologic relapse had either a CR or CR with incomplete recovery of counts (CRi), and of these 10 patients, nine were determined on follow-up to be MRD-negative by flow cytometry.
One of the two patients with extramedullary disease had a CR, and the other had a partial response.
Although two patients had no response to CD22 CAR T therapy, expression of the antigen was strong on leukemia cells from these patients, Dr. Pan said.
All patients experienced CRS, but none had greater than grade 2, Dr. Pan said, although she did not provide give specific numbers. Two patients had grade 1 neurotoxicity, two patients had grade 2 hypoxemia, and one patient had grade 2 liver enzyme elevation.
At a median follow-up of 108 days, six patients had been bridged to allogeneic HCT, and eleven of 12 patients who had a CR or CRi at 30 days had no evidence of disease progression. The remaining patient with an initial CR or CRi had a relapse at day 50. The 6-month progression-free survival rate was 91.7%.
Anton Hagenbeek, MD, PhD, from the Academic Medical Center at the University of Amsterdam, the Netherlands, who moderated the briefing but was not involved in the study, commented that given the high leukemia burden of the patients and the apparent efficacy of the therapy, one would expect to see higher grades of CRS, and asked Dr. Pan whether she could account for the CRS findings in her study, compared with those of trials for CD19-directed CAR T therapy.
It may have to do with differences in density of CD22 expression, compared with CD19 expression on leukemia cells, or on differences in the antibody used to target the cells, Dr. Pan said.
SOURCE: Pan J et al. EHA Congress, Abstract S832.
REPORTING FROM THE EHA CONGRESS
Key clinical point: A CD22-directed chimeric antigen receptor T cell construct may be a highly effective salvage therapy in children with acute lymphoblastic leukemia that has relapsed after, or is resistant to, CD19-direct CAR T therapy.
Major finding: In total, 12 of 15 children (80%) treated with the CD22 CAR T product had a complete response 30 days after infusion.
Study details: Open-label, single-center, single-arm study in 15 children with ALL that is resistant to, or relapsed after, prior CD19 CAR T therapy.
Disclosures: Dr. Pan and colleagues did not disclose a funding source for the study. She reported having no conflicts of interest.
Source: Pan J et al. EHA Congress, Abstract S832.
DLBCL survival improved with novel antibody-drug conjugate
STOCKHOLM, SWEDEN – Adding an experimental antibody-drug conjugate to bendamustine and rituximab more than doubled overall survival over bendamustine/rituximab alone in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), investigators reported.
Among 80 transplant-ineligible patients with relapsed or refractory DLBCL in a phase 2 trial, the combination of the antibody-drug conjugate (ADC) polatuzumab vedotin plus bendamustine/rituximab (BR) was associated with a 40% complete response rate, compared with 15% for BR alone.
More importantly, the ADC was associated with 6.7 months median progression-free survival (PFS) versus 2 months for BR, and 11.8 months median overall survival (OS), versus 4.7 months for BR alone, reported Laurie Sehn, MD, from BC Cancer in Vancouver, British Columbia, Canada.
“This randomized phase 2 trial really is, so far, the only head-to-head comparison of a novel targeted agent against a standard therapy in this patient population that’s ineligible for transplant, and it demonstrated that the combination polatuzumab vedotin with BR significantly improved the response rates and progression-free survival, as well as overall survival,” she said at the annual congress of the European Hematology Association.
However, in a separate cohort of patients with follicular lymphoma in the same trial, there was no difference in either PFS or OS during follow-up to date, Dr. Sehn reported.
Polatuzumab vedotin consists of an antibody targeted against CD79b, an antigenic protein expressed on the surface of normal B cells, as well as DLBCL and follicular lymphoma cells.
Dr. Sehn and her colleagues enrolled 80 patients with DLBCL for whom first-line chemoimmunotherapy had failed and who were ineligible for stem cell transplant due to age and/or comorbidities.
A second cohort included 80 patients with follicular lymphoma. In this group, median PFS with polatuzumab vedotin/BR was 17 months versus 17.3 months for BR alone, and median overall survival had not been reached in either arm at the time of the data cutoff.
In the DLBCL cohort, patients were randomized to receive polatuzumab vedotin 1.8 mg/kg plus bendamustine 90mg/m2 for 2 days and rituximab 375mg/m2) or BR alone for six 21-day cycles.
The complete response rate by PET scan – the primary endpoint – was significantly higher with polatuzmab/BR at 40% versus 15% for BR alone (P = .012). Respective overall response rates were 45% versus 18% (P = .008). Also, median PFS with the polatuzmab/BR therapy was 6.7 months versus 2.0 months for BR alone, translating into a hazard ratio of 0.31 (P less than .0001).
Respective median overall survival was 11.8 versus 4.7 months, translating into a hazard ratio for the polatuzmab/BR combination of 0.35 (P = .0008).
The PET complete response rates were higher with polatuzmab/BR regardless of prior lines of therapy or refractory status, Dr. Sehn noted.
“In terms of the safety, I think importantly in the combination there were no unexpected toxicities, so typical to what we would expect with what’s known with this drug alone,” Dr. Sehn said.
Grade 3 or greater toxicities that were higher with the polatuzmab/BR combination included cytopenias, febrile neutropenia, and infections. The single serious adverse event that had a higher incidence in the polatuzumab/BR arm was febrile neutropenia (DLBCL). In total, 12% of patients in the polatuzumab-containing arm and 11% of patients in the BR-only arm died on study. Many of the deaths were due to disease progression.
Anton Hagenbeek, MD, PhD, from the Academic Medical Center at the University of Amsterdam, the Netherlands, who moderated the briefing but was not involved in the study, said that about 20%-30% of patients with relapsed/refractory DLBCL are positive for the CD33 antigen, the target of brentuximab vedotin (Adcetris), and noted that this agent is also being tested in a phase 2 trial.
Martin Hutchings, MD, PhD, from Rigshospitalet in Copenhagen, the Netherlands, who co-moderated the oral abstract session, commented that “it’s not so often that we see significant overall survival differences in a phase 2 study with 80 patients.”
Based on the results of this trial, polatuzumab has been granted breakthrough therapy designation by the U.S. Food and Drug Administration and a PRIME (priority medicine) designation from the European Medicines Agency.
SOURCE: Sehn LH et al. EHA Congress, Abstract S802.
STOCKHOLM, SWEDEN – Adding an experimental antibody-drug conjugate to bendamustine and rituximab more than doubled overall survival over bendamustine/rituximab alone in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), investigators reported.
Among 80 transplant-ineligible patients with relapsed or refractory DLBCL in a phase 2 trial, the combination of the antibody-drug conjugate (ADC) polatuzumab vedotin plus bendamustine/rituximab (BR) was associated with a 40% complete response rate, compared with 15% for BR alone.
More importantly, the ADC was associated with 6.7 months median progression-free survival (PFS) versus 2 months for BR, and 11.8 months median overall survival (OS), versus 4.7 months for BR alone, reported Laurie Sehn, MD, from BC Cancer in Vancouver, British Columbia, Canada.
“This randomized phase 2 trial really is, so far, the only head-to-head comparison of a novel targeted agent against a standard therapy in this patient population that’s ineligible for transplant, and it demonstrated that the combination polatuzumab vedotin with BR significantly improved the response rates and progression-free survival, as well as overall survival,” she said at the annual congress of the European Hematology Association.
However, in a separate cohort of patients with follicular lymphoma in the same trial, there was no difference in either PFS or OS during follow-up to date, Dr. Sehn reported.
Polatuzumab vedotin consists of an antibody targeted against CD79b, an antigenic protein expressed on the surface of normal B cells, as well as DLBCL and follicular lymphoma cells.
Dr. Sehn and her colleagues enrolled 80 patients with DLBCL for whom first-line chemoimmunotherapy had failed and who were ineligible for stem cell transplant due to age and/or comorbidities.
A second cohort included 80 patients with follicular lymphoma. In this group, median PFS with polatuzumab vedotin/BR was 17 months versus 17.3 months for BR alone, and median overall survival had not been reached in either arm at the time of the data cutoff.
In the DLBCL cohort, patients were randomized to receive polatuzumab vedotin 1.8 mg/kg plus bendamustine 90mg/m2 for 2 days and rituximab 375mg/m2) or BR alone for six 21-day cycles.
The complete response rate by PET scan – the primary endpoint – was significantly higher with polatuzmab/BR at 40% versus 15% for BR alone (P = .012). Respective overall response rates were 45% versus 18% (P = .008). Also, median PFS with the polatuzmab/BR therapy was 6.7 months versus 2.0 months for BR alone, translating into a hazard ratio of 0.31 (P less than .0001).
Respective median overall survival was 11.8 versus 4.7 months, translating into a hazard ratio for the polatuzmab/BR combination of 0.35 (P = .0008).
The PET complete response rates were higher with polatuzmab/BR regardless of prior lines of therapy or refractory status, Dr. Sehn noted.
“In terms of the safety, I think importantly in the combination there were no unexpected toxicities, so typical to what we would expect with what’s known with this drug alone,” Dr. Sehn said.
Grade 3 or greater toxicities that were higher with the polatuzmab/BR combination included cytopenias, febrile neutropenia, and infections. The single serious adverse event that had a higher incidence in the polatuzumab/BR arm was febrile neutropenia (DLBCL). In total, 12% of patients in the polatuzumab-containing arm and 11% of patients in the BR-only arm died on study. Many of the deaths were due to disease progression.
Anton Hagenbeek, MD, PhD, from the Academic Medical Center at the University of Amsterdam, the Netherlands, who moderated the briefing but was not involved in the study, said that about 20%-30% of patients with relapsed/refractory DLBCL are positive for the CD33 antigen, the target of brentuximab vedotin (Adcetris), and noted that this agent is also being tested in a phase 2 trial.
Martin Hutchings, MD, PhD, from Rigshospitalet in Copenhagen, the Netherlands, who co-moderated the oral abstract session, commented that “it’s not so often that we see significant overall survival differences in a phase 2 study with 80 patients.”
Based on the results of this trial, polatuzumab has been granted breakthrough therapy designation by the U.S. Food and Drug Administration and a PRIME (priority medicine) designation from the European Medicines Agency.
SOURCE: Sehn LH et al. EHA Congress, Abstract S802.
STOCKHOLM, SWEDEN – Adding an experimental antibody-drug conjugate to bendamustine and rituximab more than doubled overall survival over bendamustine/rituximab alone in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), investigators reported.
Among 80 transplant-ineligible patients with relapsed or refractory DLBCL in a phase 2 trial, the combination of the antibody-drug conjugate (ADC) polatuzumab vedotin plus bendamustine/rituximab (BR) was associated with a 40% complete response rate, compared with 15% for BR alone.
More importantly, the ADC was associated with 6.7 months median progression-free survival (PFS) versus 2 months for BR, and 11.8 months median overall survival (OS), versus 4.7 months for BR alone, reported Laurie Sehn, MD, from BC Cancer in Vancouver, British Columbia, Canada.
“This randomized phase 2 trial really is, so far, the only head-to-head comparison of a novel targeted agent against a standard therapy in this patient population that’s ineligible for transplant, and it demonstrated that the combination polatuzumab vedotin with BR significantly improved the response rates and progression-free survival, as well as overall survival,” she said at the annual congress of the European Hematology Association.
However, in a separate cohort of patients with follicular lymphoma in the same trial, there was no difference in either PFS or OS during follow-up to date, Dr. Sehn reported.
Polatuzumab vedotin consists of an antibody targeted against CD79b, an antigenic protein expressed on the surface of normal B cells, as well as DLBCL and follicular lymphoma cells.
Dr. Sehn and her colleagues enrolled 80 patients with DLBCL for whom first-line chemoimmunotherapy had failed and who were ineligible for stem cell transplant due to age and/or comorbidities.
A second cohort included 80 patients with follicular lymphoma. In this group, median PFS with polatuzumab vedotin/BR was 17 months versus 17.3 months for BR alone, and median overall survival had not been reached in either arm at the time of the data cutoff.
In the DLBCL cohort, patients were randomized to receive polatuzumab vedotin 1.8 mg/kg plus bendamustine 90mg/m2 for 2 days and rituximab 375mg/m2) or BR alone for six 21-day cycles.
The complete response rate by PET scan – the primary endpoint – was significantly higher with polatuzmab/BR at 40% versus 15% for BR alone (P = .012). Respective overall response rates were 45% versus 18% (P = .008). Also, median PFS with the polatuzmab/BR therapy was 6.7 months versus 2.0 months for BR alone, translating into a hazard ratio of 0.31 (P less than .0001).
Respective median overall survival was 11.8 versus 4.7 months, translating into a hazard ratio for the polatuzmab/BR combination of 0.35 (P = .0008).
The PET complete response rates were higher with polatuzmab/BR regardless of prior lines of therapy or refractory status, Dr. Sehn noted.
“In terms of the safety, I think importantly in the combination there were no unexpected toxicities, so typical to what we would expect with what’s known with this drug alone,” Dr. Sehn said.
Grade 3 or greater toxicities that were higher with the polatuzmab/BR combination included cytopenias, febrile neutropenia, and infections. The single serious adverse event that had a higher incidence in the polatuzumab/BR arm was febrile neutropenia (DLBCL). In total, 12% of patients in the polatuzumab-containing arm and 11% of patients in the BR-only arm died on study. Many of the deaths were due to disease progression.
Anton Hagenbeek, MD, PhD, from the Academic Medical Center at the University of Amsterdam, the Netherlands, who moderated the briefing but was not involved in the study, said that about 20%-30% of patients with relapsed/refractory DLBCL are positive for the CD33 antigen, the target of brentuximab vedotin (Adcetris), and noted that this agent is also being tested in a phase 2 trial.
Martin Hutchings, MD, PhD, from Rigshospitalet in Copenhagen, the Netherlands, who co-moderated the oral abstract session, commented that “it’s not so often that we see significant overall survival differences in a phase 2 study with 80 patients.”
Based on the results of this trial, polatuzumab has been granted breakthrough therapy designation by the U.S. Food and Drug Administration and a PRIME (priority medicine) designation from the European Medicines Agency.
SOURCE: Sehn LH et al. EHA Congress, Abstract S802.
REPORTING FROM THE EHA CONGRESS
Key clinical point:
Major finding: The complete response rate with polatuzumab vedotin plus bendamustine/rituximab (BR) was 40%, compared with 15% for BR alone.
Study details: Randomized controlled phase 2 trial in 80 patients with relapsed/refractory DLBCL.
Disclosures: The study was funded by Hoffman-La Roche. Dr. Sehn reported ties to Roche/Genentech and others.
Source: Sehn LH et al. EHA Congress, Abstract S802.